Rapid and Short - A c t i n g Mealtime Insulin S e c retion With Nateglinide Controls Both Prandial and Mean Glycemia

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1 E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s O R I G I N A L A R T I C L E Rapid and Short - A c t i n g Mealtime Insulin S e c retion With Nateglinide Controls Both Prandial and Mean Glycemia MARKOLF HANEFELD, MD K. PAUL BOUTER, MD The Diabetes Intervention Study, a p rospective population-based multicenter trial of newly detected cases of type 2 diabetes, has indicated that good c o n t rol of postprandial blood glucose, blood pre s s u re, and triglycerides is associated with a lower incidence of coro n a ry SHEILA DICKINSON, MSC CHRISTIANE GUITARD, MD O B J E C T I V E The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state. RESEARCH DESIGN AND METHODS This randomized double-blind placeboc o n t rolled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA 1 c, fasting plasma glucose (FPG), fru c- tosamine, and plasma lipids were measured at pre d e t e rmined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid s t a n d a rd meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were re c o rd e d. R E S U LT S After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without aff e c t- ing triglyceride levels. At study end point, reduction of HbA 1 c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo ( 0.45, 0. 62, and 0.64%, respectively; P 0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only ( 1.14 mmol/l; P 0.01). Overall, nateglinide was well tolerated. C O N C L U S I O N S This study demonstrated that nateglinide improves mealtime and m e a n glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes. Diabetes Care 2 3 : , 2000 h e a rt disease and death (1). In addition, the U.K. Prospective Diabetes Study (UKPDS) has confirmed that intensive c o n t rol of HbA 1 c and fasting plasma glucose (FPG) in type 2 diabetic patients t reated with sulfonylureas or insulin for 10 years substantially decreased the risk F rom the Outpatient Department, Institute of Clinical Metabolic Research, Medical Faculty, Technical University of Dresden (M.H.), Dresden, Germany; Bosch Medicentre (K.P.B.), Den Bosch, the Netherlands; and N o v a rtis Pharma AG (S.D., C.G.), Basel, Switzerland. A d d ress correspondence and reprint requests to Christiane Guitard, MD, Novartis Pharma AG, Clinical R e s e a rch and Development, CME, S , CH-4002 Basel, Switzerland. p h a rm a. n o v a rt i s. c o m. Received for publication 2 July 1999 and accepted in revised form 20 October S.D. and C.G. are employed by and hold a limited number of shares in Novartis Pharma AG, which manu f a c t u res and markets pharmaceuticals related to the treatment of diabetes-related complications. A b b re v i a t i o n s : AUC, area under the plasma concentration-time curve; FPG, fasting plasma glucose; UKPDS, U.K. Prospective Diabetes Study. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. of microvascular complications (2). Howe v e r, such beneficial effects were not o b s e rved in macrovascular disease or diab e t e s - related mortality (2). Although fasting insulin and glucose levels were m e a s u red throughout the UKPDS, no prandial (mealtime) insulin or glucose data w e re available from this study. Recent publications have shown that 2-h postchallenge hyperglycemia is also associated with i n c reased total mortality (3) and coro n a ry h e a rt disease mortality (4). A recent study has suggested that prandial plasma glucose concentrations contribute to and are significantly better predictors of long-term glycemic control in diabetes than FPG (5). F u rt h e rm o re, a study of the correlations of the 30-min and 2-h plasma insulin concentrations with the 2-h plasma glucose concentration has shown that impaire d early insulin release during a meal leads to i m p a i red suppression of hepatic glucose p roduction and augmented mealtime glucose excursions (6). Thus, there is a clear need to achieve good control of prandial glucose excursions and FPG if overall diabetic morbidity and mortality are to be reduced. Curre n t l y available oral antidiabetic agents that stimulate insulin secretion do so by enhancing late insulin secretion that may induce m o d e r a t e - t o - s e v e re hypoglycemia. In contrast, nateglinide is a derivative of the amino acid D-phenylalanine (7), which is chemically distinct from other oral antidiabetic agents and acts directly on the panc reatic -cells to stimulate insulin re l e a s e that is rapid and of short duration (8). Because chronic hyperinsulinemia may a ffect body weight, plasma lipid pro f i l e, and blood pre s s u re and may there b y i n c rease the risk of cardiovascular disease (9), maintaining glucose control by i n c reasing early postchallenge insulin s e c retion without incurring chronic hyperinsulinemia is potentially advantageous. The primary objectives of this study w e re to evaluate the effects of nateglinide versus placebo on glycemic control, includi n g prandial insulin and glucose contro l, and to assess the tolerability and safety of nateglinide in patients with type 2 diabetes. 202 DIABETES CARE, VOLUME 23, NUMBER 2, FEBRUARY 2000

2 Hanefeld and Associates Figure 1 Study completion status. N, nateglinide. RESEARCH DESIGN AND M E T H O D S Study protocol This multicenter prospective randomized double-blind parallel-group study included a 4-week single-blind placebo ru n - i n s c reening period after which patients were randomized to receive double-blind tre a t- ment with either placebo or nateglinide at doses of 30, 60, 120, and 180 mg taken 10 min before breakfast, lunch, and dinner for 12 weeks. Men and women aged years with type 2 diabetes without complications who were treated with diet and exerc i s e w e re eligible for inclusion. Patients were randomized if their mean FPG level was 7.8 mmol/l and the mean level of two H b A 1 c m e a s u rements was in the range of %. Patients were excluded fro m randomization and double-blind tre a t m e n t if they had confirmed FPG 15 mmol/l and complications or concomitant tre a t- ment affecting the efficacy or safety assessments. All other antidiabetic agents were discontinued at least 3 months before rand o m i z a t i o n. Visits were perf o rmed at weeks 4, 2, 0, 2, 4, 8, and 12. Patients were maintained on their normal antidiabetic diets t h roughout the study. At baseline (week 0) and at weeks 4 and 12, a Sustacal liquid meal replaced the normal breakfast. Sustacal liquid meal was ingested 10 min after the administration of nateglinide or p l a c e b o. Drug treatment and evaluation Nateglinide was administered as either 30- or 60-mg oral tablets that were identical to the placebo tablets. In all treatment gro u p s, t h ree tablets were taken 10 min before each main meal (breakfast, lunch, and dinner), using the double-dummy method to maintain blinding. The laboratory measurements perf o rmed to assess the overall metabolic impact of diff e rent doses of nateglinide included HbA 1 c ( results standardized to the h i g h - p e rf o rmance liquid chro m a t o g r a p h y Diamat ion-exchange method), FPG (the p r i m a ry end points of the study), and f ru c- tosamine. Blood samples were obtained b e f o re medication and at 15, 30, 60, 120, 180, and 240 min after Sustacal ingestion. Levels of glucose, insulin, C-peptide, and nateglinide were measured in all samples, and triglycerides were determined in the p remedication and 120-min samples. A f a s t i n g lipid profile (total cholesterol, HDL c h o l e s t e rol, LDL cholesterol, and triglycerides) was also measured. Glucose was m e a s u red by an enzymatic method (Boehringer Mannheim, Mannheim, Germany) and a Cobas Bio analyzer (Roche Diagnostics, Basel, Switzerland). Fru c- tosamine was measured by a spectro p h o- tometric method (Roche, Basel) and a Cobas Bio analyzer. Triglyceride levels were m e a s u red with an enzymatic-re f e c t o m e t r i c method (Johnson and Johnson, Rochester, NY) using a Vi t ros 750 XR analyzer (Ort h o Clinical Systems, Rochester, NY). Levels of insulin and C-peptides were measured by radioimmunoassays (Pharmacia, Uppsala, Sweden, and DPC, Los Angeles, CA, respectively) using a Gamma-counter (Wa l- lace, Turku, Finland) and Multicalc (Wa l- lace). Safety parameters included physical e x a mination, vital signs, electro c a rd i o g r a m s, l a b o r a t o ry evaluations (hematology, c h e m- i s t ry, and urinalysis), adverse events, and self-monitoring of blood glucose levels for suspected hypoglycemia. Symptomatic suspected hypoglycemic episodes were re c o rded even if not confirmed by a low blood glucose measurement. Also, asymptomatic low fingerstick blood glucose values 2.8 mmol/l that corresponded to a plasma level 3.3 mmol/l were re c o rd e d. Statistical analysis The analysis of the HbA 1 c, FPG, Sustacal challenge data, fructosamine, and lipid variables was carried out in the intention- DIABETES CARE, VOLUME 23, NUMBER 2, FEBRUARY

3 Nateglinide versus placebo in type 2 diabetes Table 1 Demographic and glycemic parameters at baseline Nateglinide (mg) P l a c e b o n S e x M F Mean age (years) 57.4 ± ± ± ± ± BMI (kg/m 2 ) 28.3 ± ± ± ± ± 3.4 Duration of type 2 diabetes (years) 5.4 ± ± ± ± ± 3.3 Baseline FPG (mmol/l) 10.0 ± ± ± ± ± 2.1 Baseline fructosamine (µmol/l) ± ± ± ± ± 52.7 Baseline HbA 1 c (%) 8.5 ± ± ± ± ± 1.1 Data are n or means ± SD. t o - t reat population using the last observ a- tion carried forw a rd approach for those subjects who did not have a week-12 assessment in change from baseline. An analysis of variance was used to assess t reatment diff e rences. The sample size of 60 patients per treatment group was suff i c i e n t to detect a 1% change in levels of HbA 1 c versus placebo with a type 1 error of 5%, a power of 80%, and a drop-out rate of 20%. R E S U LT S Demographics and participant flow A total of 516 patients were screened, and 289 were randomized into the double-blind t reatment period (Fig. 1). Of the 289 patients randomized, almost all patients w e re Caucasian, 193 (66.8%) were men, and 73 (25.3%) were aged 65 years or o l d e r. Treatment groups were comparable at baseline with respect to demographic chara c t e r i s t i c s ( Table 1). Overall, 202 patients (69.9%) took at least one concomitant medication during the treatment period, mostly for diseases associated with diabetes, such as hypertension or hyperc h o l e s t e ro l e m i a. c o m p a red with the group administere d placebo (Table 2). Corresponding re d u c- tions in mean plasma glucose were observ e d 1 4 h postdose compared with the gro u p a d m i n i s t e red placebo (Fig. 3). The re d u c- tions from baseline (week 0) in total AUC 0 4 h for plasma glucose concentrations were statistically significant in all of the nateglinide g roups compared with the group administ e red placebo (Table 2). Nateglinide did not affect 2-h triglyceride levels after liquid meal challenge. Fasting efficacy data Mean HbA 1 c, FPG, fructosamine, and fasting lipid concentrations (total cholestero l, LDL cholesterol, HDL cholesterol, and triglycerides) at baseline were similar in all t reatment groups and remained essentially unchanged throughout the study in the placebo group. The reduction in HbA 1 c a t study end point (week 12 or last observ a- tion carried forw a rd) was statistically significantly greater than placebo in the nateglinide 60- ( 0.45%; P 0.05) and 120- and 180-mg groups ( 0.62 and 0.64%, respectively; P 0.001). A re d u c- tion in the mean FPG concentration fro m baseline was observed throughout the study in each of the nateglinide treatment gro u p s and was statistically significant in the nateglinide 120-mg group ( 1.14 mmol/l; P 0.01 vs. placebo). The reduction in mean fructosamine concentration was statistically significantly greater than with placebo in the nateglinide 60- ( µmol/l; P 0.01 vs. placebo) and 120- and 180-mg groups ( 31.4 and 35.1 µmol/l, respectively; P vs. placebo) at study end point (Table 2). Meal challenge A rapid increase in insulin secretion was o b s e rved during the liquid meal challenge. The increases were essentially dose-dependent, with maximal values observed 30 min postdose and a re t u rn to predose levels within 3 4 h (Fig. 2). The increase from baseline (week 0) in total area under the plasma concentrationtime curve (AUC 0 4 h ) for insulin and C-peptide was statistically significant in the nateglinide 60-, 120-, and 180-mg gro u p s Figure 2 Adjusted mean change versus baseline in prandial plasma insulin at week DIABETES CARE, VOLUME 23, NUMBER 2, FEBRUARY 2000

4 Hanefeld and Associates Table 2 Changes in meal challenge data and HbA 1 c, FPG, and fructosamine concentrations at study end point Nateglinide (mg) P l a c e b o Meal challenge parameters (change from baseline) n A U C 0 4 h glucose (h mmol l 1 ) 3.2 (0.3 to 6.0) 3.6* ( 6.4 to 0. 8 ) 8.0* ( 10.6 to 5. 5 ) 8.5* ( 11.0 to 5.9) 8.1* ( 10.8 to 5. 4 ) A U C 0 4 h insulin (h mu l 1 ) 6.0 ( 8.7 to 20.7) 19.0 (4.2 to 33.9) 35.5 (22.3 to 48.8) 49.1* (35.8 to 62.3) 46.2* (32.4 to 59.9) A U C 0 4 h C-peptide (h pmol m l 1 ) 0.2 ( 0.7 to 0.4) 0.4 ( 0.2 to 0.9) 1.2* (0.7 to 1.7) 1.8* (1.3 to 2.3) 1.6* (1.1 to 2.1) Mean glycemia parameters n H b A 1 c (%) 0.07 ( 0.18 to 0.32) 0.20 ( 0.48 to 0.07) 0.38 ( 0.62 to ) 0.55 ( 0.79 to ) 0.56 ( 0.81 to ) D i ff e rence from placebo 0.27 ( 0.65 to 0.10) 0.45 ( 0.80 to ) 0.62 ( 0.97 to ) 0.64 ( 0.99 to ) FPG (mmol/l) Change from baseline 0.22 ( 0.27 to 0.72) 0.42 ( 0.95 to 0.12) 0.46 ( 0.94 to 0.02) 0.92 ( 1.40 to ) 0.56 ( 1.05 to ) D i ff e rence from placebo 0.64 ( 1.37 to 0.08) 0.69 ( 1.37 to 0.00) 1.14* ( 1.83 to ) 0.79 ( 1.48 to ) F ructosamine (µmol/l) Change from baseline 7.7 ( 2.8 to 18.3) 0.4 ( 11.0 to 11.8) 16.2 ( 26.9 to 5. 6 ) 23.7 ( 33.8 to ) 27.3 ( 37.4 to ) D i ff e rence from placebo 7.4 ( 22.9 to 8.14) 24.0* ( 38.9 to ) 31.4 ( 46.0 to ) ( 49.6 to ) Data are n or means (95% CI). Changes versus placebo (analysis of variance model): *P 0.01, P 0.05, P No statistically significant diff e re n c e s between the nateglinide and placebo gro u p s in the concentrations of any of the seru m lipids were observed at study end point. Safety A total of 6 patients (10.0%) in the placebo g roup and 18 patients (7.9%) in the pooled nateglinide group did not complete the s t u d y. However, the discontinuation rates for adverse events were low in both gro u p s (two patients [3.3%] in the placebo gro u p and five patients [2.2%] in the pooled nateglinide group). One patient in the nateglinide 180-mg group was discontinued because of elevated liver function tests (gamma-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase) that were considered to be possibly related to the study drug and that re t u rned to normal at the follow-up visit. One patient in the nateglinide 30-mg gro u p with a history of chronic coro n a ry art e ry disease died from myocardial infarc t i o n ascribed to coexistent disease; his death, t h e re f o re, is considered unlikely to be related to the study dru g. The incidence of adverse events for all randomized patients was higher in the pooled nateglinide group (49.3%) (n = 229) compared with the placebo gro u p (35.0%) (n = 60). Although there were m o re adverse events judged as possibly or p robably related to treatment re p o rted for patients in the pooled nateglinide gro u p than in the placebo group, the incidence of events was not dose dependent. Most of the events were mild symptoms suggestive of hypoglycemia, such as increased sweating (n = 16 [7.0%]), tremor (n = 14 [6.1%]), dizziness (n = 7 [3.1%]), increased appetite (n = 6 [2.6%]), and asthenia (n = 4 [1.7%]). Only three patients in the 120-mg gro u p with events suggestive of hypoglycemia had a blood glucose value in the Figure 3 Adjusted mean change in prandial glucose at week 12. mmol/l range, but no patients were discontinued for hypoglycemia. The pre d o m- inant causes of symptoms suggestive of hypoglycemia were strenuous exercise or a missed or delayed meal. All such events o c c u rred during the daytime, and most patients re c o v e red within 15 min. A patient f rom the nateglinide 30-mg group with suspected serious hypoglycemia experienced a fall with a short loss of consciousness 5 h after medication and meal intake; h o w e v e r, she re c o v e red spontaneously and DIABETES CARE, VOLUME 23, NUMBER 2, FEBRUARY

5 Nateglinide versus placebo in type 2 diabetes completed the study uneventfully. A blood glucose measurement was not perf o rmed at the time of the event. Hematologic and biochemical analyses did not reveal further diff e re n c e s between the treatment groups. There were no relevant electro c a rdiogram abnorm a l i- ties or changes in vital signs. Changes in body weight ranged from 0.38 to 0.72 kg in the nateglinide 120-mg gro u p. C O N C L U S I O N S The study population was re p resentative of mild to moderately severe type 2 diabetes with mean baseline HbA 1 c values of %. The mean FPG values at baseline were in the range between 9.9 and 10.3 mmol/l, and o n e - q u a rter of the study population was aged 65 years and older. Only small changes versus baseline were observed in the placebo g roup, because stable baseline levels of glycemic control were established by using a long washout period in patients pre v i o u s l y on oral antidiabetic treatment (HbA 1 c i n c rease from baseline at study end point in the placebo group was only 0.07%). Administration of mg of nateglinide before meals consistently d e c reased all parameters of glycemic cont rol, such as mealtime glycemia, FPG, fru c- tosamine, and HbA 1 c, compared with placebo at end point and from baseline. The results of the liquid meal challenge c o n f i rmed the rapid onset of prandial insulin secretion with high insulin levels p resent 15 min postdose and maximal plasma concentrations observed min postdose. Defects in early insulin secretion in patients with type 2 diabetes or at incre a s e d risk for diabetes were first identified in the 1960s (10). These abnormalities contribute to prandial hyperglycemia and late hyperglycemia, which lead to marked delay in the inhibition of hepatic glucose pro d u c- tion (5,6). These defects were also observ e d in the patients of this study who were a d m i n i s t e red placebo. The administration of nateglinide induced a rapid stimulation of insulin secretion of short duration with relevant changes between placebo and active arms between 15 and 30 min after d rug intake. Insulin levels re t u rned to baseline values 3 4 h after drug intake. The induction of early insulin secretion with nateglimide offers an advantage over glyburide, which does not have any appre c i a- ble effect on early-phase insulin secre t i o n but enhances late insulin secretion in patients with type 2 diabetes (11), and repaglinide, which produces a longer duration of insulin stimulation (12). The rapid and relevant increase in insulin secretion after nateglinide administration blunted the sharp rise in glucose that follows a meal as indicated by the 1- to 4-h postmeal decreases in glucose excursions. The decreases in parameters assessing mean glucose exposure, such as HbA 1 c and fru c- tosamine, reflect decreases in mealtime glycemia. Nateglinide showed a relatively small e ffect on FPG. This might reflect an indire c t rather than a direct effect on hepatic glucose p roduction given the short duration of insulin stimulation that was observed with all tested doses of nateglinide. Mealtime glucose excursions have been shown to make a major contribution to overall poor glycemic control in type 2 diabetes (5), and the rapid-onset/short - duration insulin-release profile seen with nateglinide after liquid meal challenge appears to mimic the physiological early phase of insulin release that is deficient in patients with type 2 diabetes. Similar o b s e rvations have been made with a short - acting insulin (13). F u rt h e rm o re, mealtime and postchallenge glucose have been shown to be linked with an increased risk of overall m o rtality (3) and an increased risk of diabetic complications, such as nephro p a t h y, re t i n o p a t h y, neuro p a t h y, athero s c l e ro s i s, and myocardial infarction (1,14,15). Tre a t- ments aimed at reducing mealtime glycemic excursions as monotherapy or in combination with drugs having a complem e n t a ry mode of action may further contribute to alleviating the burden on patients with type 2 diabetes. Overall, nateglinide was well tolerated. The most common adverse events were equally distributed among the diff e re n t t reatment groups with the exception of predominantly mild symptoms suggestive of hypoglycemia in the pooled nateglinide g roup. Most symptoms of hypoglycemia w e re not associated with low blood sugar values and can there f o re be classified as re l- ative hypoglycemia. Confirmed hypoglycemia (blood glucose value 3.3 mmol/l), was observed in three patients (1.3%). In conclusion, this study has demonstrated that nateglinide improves glycemic c o n t rol in a dose-dependent manner t h rough increased mealtime insulin secretion. Nateglinide seems to be part i c u l a r l y e ffective in restoring early insulin secre t i o n in response to a meal, which is of cru c i a l i m p o rtance for regulation of the postprandial state. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes. A c k n o w l e d g m e n t s This re s e a rch was supp o rted by a grant from Novartis Pharma AG and was previously presented in two posters at the 34th Congress of the European Association for the Study of Diabetes in Barcelona, Spain, September R e f e re n c e s 1. 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6 Hanefeld and Associates centrations in nondiabetic and in early diabetic subjects: determinations by a new sensitive immuno-assay technique. D i a b e t e s 9: , G roop LC: Sulfonylureas in NIDDM. D i a - betes Care 15: , L e c l e rq-meyer V, Ladriere L, Fuhlendorff J, Malaisse WJ: Stimulation of insulin and somatostatin release by two meglitinide analogs. E n d o c r i n e 7: , B ruttomesso D, Pianta A, Mari A, Valerio A, M a rescotti MC, Av o g a ro A, Tiengo A, Del Prato S: Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetes patients. D i a b e t es 48:99 105, Yamasaki Y, Kawamori R, Matsushima H, Nishizawa H, Kodama M, Kabota M, Kajimoto Y, Kamada T: Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the caro t i d a rt e ry. D i a b e t o l o g i a 38: , E x p e rt Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. D i a - betes Care 20: , 1997 DIABETES CARE, VOLUME 23, NUMBER 2, FEBRUARY